Hidradenitis suppurativa (HS) is a chronic skin disease and severe form of acne (acne inversa). HS affects the apocrine sweat glands that often results in chronically draining sinus tracks and wounds. Genetics plays a significant role in the etiology of HS. Presenilins (PSEN1 and PSEN2) encodes homologous PS1 and PS2 proteins, which are components of - secretase complex and responsible for intramembranous cleavage of various type I membrane proteins. PSEN1-P242LfsX11 mutation has been found in patients with familial HS. In addition to HS, mutations in presenilins have been found in patients with early-onset familial Alzheimer's disease (AD) and patients with dilated cardiomyopathy (DCM), indicating allelic heterogeneity. However, to date how a mutation in PSEN1 leads to HS pathogenesis remains elusive. The root cause of HS appears to be apocrine gland dysfunction. Drosophila salivary gland undergoes apocrine secretion process and programmed cell death. Therefore Drosophila provides an effective in vivo genetic tool for modeling HS pathogenesis. The human presenilins are represented by a highly conserved ortholog, dPsn, in Drosophila. We have employed transgenic Drosophila model to examine the effect of change in dPsn expression (dPsn null mutant, overexpression or RNAi silencing) in larval salivary gland. We have found that dPsn is expressed in the salivary gland cell and change in dPsn expression leads to defected secretory cell with disrupted secretory granules. These indicate that dPsn is required for maintaining apocrine gland structure and secretory function. We propose to further characterize the effects of change in dPsn expression on apocrine secretion activity, programmed cell death and immunity. We will also determine the effect of HS-associated PSEN1-P242LfsX11 mutation in comparison with that of an AD- or DCM-associated PSEN1 mutation, which will reveal the functional differences between HS-, AD- or DCM-associated PSEN1 mutations. These studies will shed new insight on the functional role of presenilin and -secretase complex in HS pathogenesis. PUBLIC HEALTH RELEVANCE: Narrative Statement Hidradenitis suppurativa (HS) is a severe form of acne (acne inversa). Mutation has been found in presenilin 1 in patients with familial HS. We propose to characterize the functional role of presenilin 1 in HS pathogenesis for the identification of novel therapeutic targets.